WO2004103565A2 - Dispositif et procede de structuration de liquides et de dosage de liquides de reaction vers des compartiments a liquides noyes dans un fluide de separation - Google Patents

Dispositif et procede de structuration de liquides et de dosage de liquides de reaction vers des compartiments a liquides noyes dans un fluide de separation Download PDF

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Publication number
WO2004103565A2
WO2004103565A2 PCT/DE2004/001056 DE2004001056W WO2004103565A2 WO 2004103565 A2 WO2004103565 A2 WO 2004103565A2 DE 2004001056 W DE2004001056 W DE 2004001056W WO 2004103565 A2 WO2004103565 A2 WO 2004103565A2
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Prior art keywords
liquid
microchannel
liquids
separation medium
compartments
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Ceased
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PCT/DE2004/001056
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German (de)
English (en)
Other versions
WO2004103565A3 (fr
Inventor
Gunter Gastrock
Andreas Grodrian
Thomas Henkel
Mark Kielpinski
Michael KÖHLER
Karen Lemke
Karin Martin
Josef Metze
Martin Roth
Thore Schön
Volker Baier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Institut fuer Bioprozess und Analysenmesstechnik eV
Institut fuer Physikalische Hochtechnologie eV
Leibniz Institut fuer Naturstoff Forschung und Infektionsbiol eVi
Technische Universitaet Ilmenau
Original Assignee
Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Institut fuer Bioprozess und Analysenmesstechnik eV
Institut fuer Physikalische Hochtechnologie eV
Leibniz Institut fuer Naturstoff Forschung und Infektionsbiol eVi
Technische Universitaet Ilmenau
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2003122893 external-priority patent/DE10322893A1/de
Priority claimed from DE10339452A external-priority patent/DE10339452A1/de
Application filed by Hans-Knoll-Institut fur Naturstoff-Forschung Ev, Institut fuer Bioprozess und Analysenmesstechnik eV, Institut fuer Physikalische Hochtechnologie eV, Leibniz Institut fuer Naturstoff Forschung und Infektionsbiol eVi, Technische Universitaet Ilmenau filed Critical Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Priority to DE112004001376T priority Critical patent/DE112004001376D2/de
Publication of WO2004103565A2 publication Critical patent/WO2004103565A2/fr
Publication of WO2004103565A3 publication Critical patent/WO2004103565A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/7176—Feed mechanisms characterised by the means for feeding the components to the mixer using pumps
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles or throttle valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
    • B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/7174—Feed mechanisms characterised by the means for feeding the components to the mixer using pistons, plungers or syringes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/80—Forming a predetermined ratio of the substances to be mixed
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/08—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/165—Specific details about hydrophobic, oleophobic surfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves

Definitions

  • the invention relates to a device and a method for structuring liquids and for metering reaction liquids into liquid compartments embedded in the separation medium, in particular for high-throughput analysis methods in microsystem technology.
  • document DE 298 01 523.4 discloses a pipette or microreactor consisting of at least one capillary channel which is formed by a trench which is introduced into a substrate and can be covered by means of a microstructuring method and which is connected on one side to a pressure chamber, a controllable electrical heating medium in the pressure chamber Form of a thin-film heating resistor applied to an outer wall of a pressure chamber wall in the form of a rigid membrane is assigned and an area of the connection between the capillary channel and the pressure chamber is provided with heat sink means and the capillary channel receives a liquid column or a plunger.
  • the document WO 98/16312 discloses a pipette which is provided in the pipette tip area with an integrated closure means and with at least one filter element.
  • a microdosing device for the defined delivery of small, self-contained liquid volumes is known from DE 100 10 208.5-52.
  • HPLC high pressure liquid chromatography
  • the document DE 101 45 568.2 discloses a method for the parallel cultivation of microorganisms in microcapillaries in a liquid two-phase system, liquid segments serving as recreation rooms for microorganisms to be cultivated.
  • microsystem-technical methods and devices consists in addressably structuring liquids carried in microcapillaries into defined concentration spaces within a liquid flow and metering reagents in a targeted manner into these concentration spaces (liquid compartments).
  • the invention is based on the object of specifying a device and a method for structuring liquids for analytical, microbiological and cell biological as well as (bio) chemical-combinatorial applications, which address liquids in microcapillaries and addressable structures in defined concentration spaces within a liquid flow and reagents direct to these concentration areas (liquid compartments).
  • FIG. 1 shows the schematic representation of a device according to the invention
  • FIG. 2 shows the schematic representation of a second embodiment of the device according to the invention
  • FIG. 3 shows the schematic representation of a third embodiment of the device according to the invention
  • FIG. 5 shows the schematic representation of a fifth embodiment of the device according to the invention
  • Fig. 6 is a schematic representation of a sixth
  • Fig. 7 is a schematic representation of a seventh
  • FIG. 8 shows the schematic representation of an eighth embodiment of the device according to the invention.
  • phase 9 the schematic representation of a dosing device during the dosing process (phase 1)
  • phase 2 the schematic representation of a dosing device during the dosing process
  • FIG. 11 shows the schematic representation of a dosing device during the dosing process (phase 3)
  • FIG. 12 shows the schematic representation of a dosing device during the dosing process (phase 4)
  • Figure 13 is a schematic representation of a conveyor in side view and sectional view along A-A
  • FIG. 15 the schematic representation of a microchannel course
  • (Detail) 16 shows the schematic representation of a device according to the invention for titration analysis
  • the device for structuring liquids consists of predetermined liquid guidance paths (1), at least one metering device (4) opening into the liquid guidance paths (1) (shown in FIG. 6) and in the liquid guidance paths (1) at least one fusionator (2) and / or splitter (3) is arranged.
  • the liquid conduits (1) are particularly advantageously designed as channels or tubes in the form of microstructures, fluid resistors (6) being provided in the area of the fusionator (2) and splitter (3), which are connected to a separation chamber (7) (shown in FIG 3) can open.
  • the dosing device (4) (shown schematically in FIG. 6) is designed as a mechanically, electrically or thermally controllable valve or as a microchannel which can be filled periodically with solid and / or liquid substrate and / or gas.
  • the fusionator (2) and the splitter (3) are each formed by at least one branch within the liquid guide paths (1), in the immediate vicinity of which there are advantageously fluid resistors (6).
  • At least one nozzle (5) can open into the gapator (3), which is particularly advantageously provided with a separation chamber (7) at this point (shown in FIG. 3), which leads into the liquid conduits (1).
  • This nozzle (5) can be flowed through in a pulsed manner with liquids or gases, it being possible for it to be arranged centrally or concentrically in a branching of the liquid guide paths (1).
  • the essence of the method for structuring liquids along predetermined liquid routes, in which the device according to the invention is used, is the combination between largely monotonous (ie continuously) variable flow rates through conventional fluid actuators (eg syringe pumps or Micropumps) and a kind of "digitization" of the sample manipulation or the synthesis volumes through the segmentation and the subsequent manipulation of individual liquid segment streams (segment sequences).
  • fluid actuators eg syringe pumps or Micropumps
  • digitalization of the sample manipulation or the synthesis volumes through the segmentation and the subsequent manipulation of individual liquid segment streams (segment sequences).
  • liquid segments (9) can also be formed by synchronously superimposed monotonically and periodically variable flow rates in, for example, computer-controlled fluid actuators in modular fluid systems
  • compositions are generated that cover areas of concentration or concentration ratios, which is very important for combinatorial chemistry or for screening processes under the synergetic effect of effectors.
  • the fusion device (2) which has two fluid conduits (1) in one, a fluid resistance (6) comprehensive, downstream liquid guide paths (1), the fluid resistance (6) being located in the immediate vicinity of the branching of the liquid guide paths (1) (FIG. 1), the fusion of segments located in two flowing liquids is possible in the device according to the invention ,
  • the separation chamber (7) of the splitter (3) which is provided with two or more pulse channels (8) for the pulsed introduction of liquid or gas into the separation chamber (7), is also a synchronous one Multiple division of the liquid segments (9) possible.
  • thermally modulated fluid-resistant fluid control can also be used in the device according to the invention.
  • a bypass arrangement FIG. 7
  • critical passenger resistances or carrier flows in the main liquid guide path (1) for the liquid segments (9) can be set by means of an electrically controlled thermally controlled viscosity in the bypass (10) (FIG. 7).
  • liquid segments (9) can be synchronized, controlled, held, released, possibly also split or fused, whereby the combination with separation chambers (7) and fluid resistors (6) can take place.
  • a combination of two bypasses (10) with a separation chamber (7) and fluid resistors (6) (not shown in more detail) is advantageous for stopping liquid segments (9) that are tolerant of segment sizes.
  • thermally controlled segment switch By combining thermal fluid control with a branching structure, advantageously provided with fluid resistors (6), a thermally controlled segment switch can also be implemented (FIG. 8).
  • the combination of the elements mentioned 8, as indicated schematically in FIG. 8, allows the construction of complex controllable channel architectures (microfluidic networks for entire populations of "fluidic sequences"), which are used, for example, in the microbiological and combinatorial screening of microorganism cultures against complex sets of stress factors.
  • Inorganic synthesis and screening for example in the coprecipitation of poorly soluble transition metal compounds for catalyst development, are also areas of application of the device and the method according to the invention.
  • the microchannel (11) with dosing device (4) is a central functional element which serves to transport the sequences of liquid compartments (115) embedded in the separation medium and in which one or more of second microchannels (14) opens, which has the task of metering the process liquid contained therein by means of a metering device (4) to the liquid compartments guided in the microchannel (11).
  • FIGS. 9 to 12 The course of metering is shown in FIGS. 9 to 12.
  • sequences of compartments are led past the mouth of the microchannel (14) (FIG. 9).
  • This metering is carried out by temporarily fusing a liquid compartment from the microchannel (11) with a process liquid (15) in the region of the mouth of the microchannel (14), shown in FIG. 10, in connection with the conveyance of the process liquid (15) with the aid of a suitable one Conveying device (19) (Fig. 13) achieved, as shown in Fig. 11.
  • the compartment is torn off (117 in FIG. 12), mediated by conveying the separation medium in the microchannel (11). This process can take place both continuously and discontinuously.
  • the defined drop tear-off forms the prerequisite for a high reproducibility and accuracy of the metered volume and thus determines the process reliability of the dosing process.
  • the energy input to be carried out for the controlled demolition of the fluid compartment corresponds to the sum of the interfacial energy to be generated for the production of the new interfaces in the region of the confluence of the microchannel (14) into the microchannel (11) and the surface to be newly created on the compartment and can be describe first approximation through the context
  • the arrangement according to the invention and the coordination according to the invention the dimensions of the microchannels, opening widths of the mouth, wetting properties of the surfaces for the specified liquids and the preferred shape of the mouth as a sharp-edged narrowing of the microchannel (14).
  • the arrangement according to the invention is particularly due to the sharp-edged design the entrance opening on both sides in the direction of the microchannel (11) effectively prevents the phase boundary from migrating into this channel.
  • the following criteria which define the wetting behavior of the inner surfaces in the area where the microchannel (14) opens into the microchannel (11), are required for reliable process control. These conditions may have to be implemented by suitable chemical surface functionalization and the coordination of the selection of the components used. The determination is made on the basis of the contact angle of the ternary systems, for the determination of which measuring devices are offered on the market.
  • the contact angle (114), determined according to FIG. 14, for a ternary system of liquid A (111), liquid B (112) and surface (HO) for the system test liquid (13), separation medium (12) and inner surface of the Micro channel (11) exceed 90 °, for the process liquid system (15),
  • Separation medium (12) and inner surface of the microchannel (11) exceed 60 °, and for the system separation medium (12), mixture (17) and inner surface of the microchannel (11) exceed 90 °, for the system separation medium (12), process liquid (15 ) and the inner surface of the microchannel (14) exceed 60 °.
  • the individual dosing of substances to individual and defined compartments, a series of compartments in connection with the use of one or more microchannels (14) is necessary for universal use of the method and the arrangement. According to the invention, this is achieved by reversing the conveying direction of the process liquid in question into the associated microchannel (14) in such a way that the phase boundary between the separation medium and process liquid shifts into the microchannel (14) and thereby the possibility of fluidic contact between in the microchannel (11) located compartments and the process liquid (15) located in the microchannel (14) is prevented.
  • FIG. 16 An arrangement according to FIG. 16 is used for the aforementioned determination, in which a microchannel (11) is guided through two microchannel chips and is fluidly connected on one side to a syringe pump for conveying the separation medium (SP) tetradecane, presented in a 5 ml glass syringe ,
  • SP separation medium
  • a second syringe which contains the test liquid (13), is fixed in the second receptacle of the syringe pump and is fluidly connected to a microchannel opening into the microchannel (11).
  • This system is used for the coupled delivery of separation medium and test liquid with a delivery ratio of tetradecane to test liquid of 5: 1.
  • a 1 ml syringe filled with process liquid (15) is fluidly connected to the microchannel (11) via a microchannel (14), the process liquid being conveyed independently of the conveyance of the first syringe pump.
  • the arrangement according to the invention realized as a microchip is characterized by the following parameters: width of the microchannel (11): 740 ⁇ m, height of the microchannel (11): 280 ⁇ m, width of the microchannel (14): 320 ⁇ m, height of the microchannel (14): 280 ⁇ m, all channel cross sections have the shape of a rectangle, the corners of which are rounded with a radius of 140 ⁇ m.
  • the opening of the opening of the microchannel (14) into the microchannel (11) is 70 ⁇ m x 300 ⁇ m (height x width). Capillaries made of PTFE were used to connect the chips.
  • the surfaces of the chip modules made of glass, were activated with a mixture of 25 vol% hydrogen peroxide and 75 vol% sulfuric acid, washed with water, dried in a drying cabinet at 120 ° C and in a solution of 2 mM octadecyltrichlorosilane in anhydrous toluene for 3 hours Implemented room temperature and rinsed with toluene and then ethanol.
  • the contact angle determined on an identically rinsed glass surface for the water / tetradecane / surface system according to FIG. 14 is 150 ° and corresponds to the criteria for the arrangement according to the invention and the method according to the invention.
  • compartments are continuously formed in the microchannel (11) of hydrochloric acid with a volume of 130 nl and a rate of 1.07 Hz.
  • the compartment volume is calibrated on the basis of the previously determined dependency of the compartment volume on the flow rate for the chip used in the experiment. This is shown as a box & whisker plot in FIG. 17.
  • the microchannel (11) is passed via an HPLC capillary with an inner diameter of 0.5 mm into an injection chip, through the microchannel (14) of which sodium hydroxide solution is continuously metered in at a concentration of 0.05 mol / l.
  • the delivery rate is gradually increased in increments of 0.1 ml.
  • the equivalence point can be recognized by a change in color of the indicator bromophenol blue to hydrochloric acid added to blue and is detected with a CCD camera and an upstream interference filter in the wavelength range 575 to 625 nm.
  • the color change is observed in 32 of 50 compartments (64%)
  • the color change takes place in 50 of the 50 compartments observed (100%).
  • the method was used analogously to the determination of the citric acid concentration by titration against sodium hydroxide solution.
  • the device according to the invention and the method according to the invention enable simple, rapid, reliable and inexpensive structuring of liquids for analytical, microbiological and cell biological as well as (bio) chemical-combinatorial applications that addressably structure liquids carried in microcapillaries into defined concentration spaces within a liquid flow.
  • the device and the method according to the invention firstly provide access to the generation of sample streams with a large number of different contents located in different compartments using principles of combinatorial chemistry or for the production of clones of pro or eukaryotic cells by culturing the each with a single cell inoculated liquid compartments, and on the other hand they enable the serial addition of test reagents, the serial analysis of the contents of the compartments and their change as a result of the addition of a component and carrying out cellular assays using compartments inoculated with a uniform cell population in connection with the metering of effectors. By adding different volumes, dose-effect dependencies can be investigated with the method according to the invention.

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  • Health & Medical Sciences (AREA)
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  • Clinical Laboratory Science (AREA)
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  • General Physics & Mathematics (AREA)
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  • Physical Or Chemical Processes And Apparatus (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un dispositif et un procédé de structuration de liquides et de dosage de liquides de réaction vers des compartiments à liquides noyés dans un fluide de séparation. L'invention vise à mettre en oeuvre un dispositif et un procédé de structuration de liquides destinés à des applications analytiques, des applications de microbiologie et de biologie cellulaire, et des applications (bio)chimiques combinatoires, permettant de structurer des liquides guidés dans des microcapillaires, de façon adressable dans des zones de concentration définies, et d'acheminer des réactifs de façon ciblée vers ces zones de concentration (compartiments à liquides). A cet effet, ledit dispositif est composé de chemins de guidage de liquide prédéfinis dans lesquels aboutit au moins un dispositif de dosage et/ou contenant au moins un fusionneur et/ou un séparateur.
PCT/DE2004/001056 2003-05-19 2004-05-18 Dispositif et procede de structuration de liquides et de dosage de liquides de reaction vers des compartiments a liquides noyes dans un fluide de separation Ceased WO2004103565A2 (fr)

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